Fronto-temporal dementia (FTD) is a heterogeneous condition characterized by early behavioral change, cognitive decline and atrophy of the frontal and temporal lobes. The microscopic pathology varies markedly in different forms of the disease with some cases having tau-positive neuronal inclusions. However, the majority of FTD cases (approximately 60%) lack tau-positive lesions displaying mainly a microvacuolization of the superficial neuropil in the cortex. A proportion of these cases (10-15%) however do have ubiquitin-positive inclusions in motor neurons and show evidence of motor neuron degeneration (MND) leading to their designation as FTD-MND cases. Genetic linkage studies in FTD families have revealed three loci on chromosomes 17, 3 and 9. Over 30 mutations in the tau gene account for the majority of autosomal-dominant chromosome 17-1inked cases (FTDP-17). FTDP-17 patients with identified tau mutations develop tau neurofibrillary pathology and many families also develop tau inclusions in glial cells. Recently a locus on chromosome 9q21-22 (chr.9q21-22) was reported by Hosler and colleagues in families with affected members with both FTD and MND. The occurrence of the disease in these families is consistent with an autosomal dominant pattern of inheritance. We have examined our own families with FTD-MND and have also found evidence of linkage to the same locus on chr. 9 in these families. In addition, we have used haplotype analysis in a series of families from Northwest England to suggest a reduced approximate 7 cM critical region on chr9q21-22. The overall aim of this proposal is to identify gene mutations associated with FTD-MND linked to chr.9q21-22 and to study the genotype/phenotype relationship and pathogenic mechanism of mutations in this gene. The identification of this gene will be a crucial step towards understanding the etiology of FTD as well as determining how this disease relates to MND.